MK-801- and ethanol-induced activity in inbred long-sleep and short-sleep mice: dopamine and serotonin systems

Low doses of (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801; dizocilpine) or ethanol induce less locomotor activation in inbred long-sleep (ILS) than short-sleep (ISS) mice. These differences may involve altered dopamine and/or 5-hydroxytryptamine (serotonin; 5-HT) neurotransmission. To address this possibility, the dopaminergic and serotonergic mechanisms underlying the locomotor-stimulant effects of MK-801 and ethanol in ILS and ISS mice were studied. Dopamine D1, D2 and 5-HT(2A) receptor antagonists reduced MK-801-stimulated activity in ILS mice without having any effect in ISS mice. The 5-HT reuptake inhibitor fluoxetine potentiated MK-801-stimulated activity selectively in ILS mice. Strain differences in 5-HT transporters do not explain this selective effect of fluoxetine in ILS mice since [3H]citalopram binding and [3H]5-HT uptake studies found no differences in the affinity, number or function of 5-HT transporters between ILS and ISS mice. Ethanol-induced activity in ISS mice was depressed by dopamine D2 and 5-HT(2C) receptor antagonists and enhanced by a 5-HT(1A) receptor antagonist. These results suggest that in ILS mice the locomotor-stimulant effects of MK-801 require increased dopamine and/or 5-HT neurotransmission. Conversely, in ISS mice, the effects of MK-801 appear to be monoamine-independent. Thus, even though both MK-801 and ethanol inhibit N-methyl-D-aspartate receptors, their stimulant effects appear to involve different neuronal systems.